Huntington's disease (HD) is a fatal, autosomal dominant neurodegenerative disorder of mid-life onset, characterized by chorea, cognitive abnormalities and progressive dementia. The underlying genetic defect is an expanded trinucleotide CAG repeat. No disease modifying therapies are available. Polyglutamine misfolding and aggregation have been implicated as plausible causes ofthe marked neurodegeneration; however, the therapeutic promise of aggregate inhibition has yet to be realized. We have identified small molecule inhibitors of polyglutamine aggregation in high throughput screening. Hit optimization in neuronal PCI 2 cells yielded two sulfobenzoic acid derivatives, 02-8 and AK-1, as potential therapeutic leads. ADMET profiling of 02-8 has been consistent with excellent drug-like properties. 02-8 inhibits polyglutamine aggregation in R6/2 mouse brain slices, while reversing the effects of neurodegeneration in a fruit fly model of HD. Further investigation shows that 02-8 is non-toxic, has favorable brain pharmacokinetics, reduces huntingtin aggregate size and number in vivo, is neuroprotective as measured by behavioral and neuropathological outcome measures, and significantly extends survival in R6/2 HD mice while reducing striatal neuron loss. 02-8 administration in the full-length knock-in 140 CAG mouse HD model show improved motor performance throughout disease progression with a significant reduction in huntingtin aggregates. Encouraged by the 02-8-mediated efficacy in HD mouse models, pharmacokinetic assays were carried out on two lead structural analogs, selected based on in silico calculations of their oral bioavailability. Both analogs have more favorable blood-brain-barrier penetration properties than 02-8, demonstrating the feasibility of significantly improving upon 02-8 and AK-1 as therapeutic leads through medicinal chemistry development. Accelerating the pace to bring drugs to clinical trials in humans is an important and achievable goal. From the studies performed in years 1-3, we will select one lead, establish GMP synthesis, and perform GLP ADMET studies during years 4 and 5, followed by an IND application by the end of year 5. PUBLIC HEALTH RELEVANCE: Huntington's disease is a fatal progressive neurodegenerative disorder for which there are treatments proven to slow the disease course. We have identified novel drug-like compounds that modulate the causative abnormal protein and which are neuroprotective in HD models. Our goals in this project are to optimize these compounds, ready the most promising for clinical trials in humans by performing IND-enabling studies, and engaging the FDA with our data and plans withan IND submission.